Normal excitation-contraction (EC) coupling in mammalian cardiac cells requires the coordinated release of calcium (Ca2+) from the sarcoplasmic reticulum (SR). In mammalian ventricular cells, the extensive transverse-tubular (t-tubular) system conducts electrical depolarization rapidly to the cell interior that triggers a near synchronous release of C2+ from the SR and subsequent activation of the myofibrils throughout the cell. Because atrial cells lack an extensive t-tubular network, the coordination of SR Ca2+-release and contraction in atrial cells must depend on an entirely different cellular process. The aim of the proposed research is to answer the question, "What is (are) the cellular mechanism(s) responsible for the transduction of membrane depolarization to subsequent contraction in cardiac atrial cells?" The overall hypotheses of this proposed project are (1) that the mechanism of coupling Ca2+-entry through L-type Ca2+ channels and Ca2+-release from the SR at the peripheral couplings of atrial cells is the same as that which occurs at the t-tubular-junctional SR region in ventricular cells, and (2) that because of the absence of a well-organized t-tubular system in atrial cells, the normal physiological mechanisms of SR Ca2+-release away from the peripheral couplings are entirely different. Specific aim 1 tests the hypothesis that the relationship between Ca2+-entry via L-type Ca2+ channels and Ca2+-release from the SR at the peripheral couplings in atrial cells is identical to that in the t-tubular-junctional SR region of ventricular cells. Specific aim 2 tests the hypothesis that both propagated and non-propagated Ca2+-release occur in atrial cells and that the type of Ca2+-release is determined by SR Ca2+-load, ryanodine receptor (RyR) Ca2+-sensitivity, and the magnitude and duration of the Ca2+-entry through L-type Ca2+ channels. Specific aim 3 tests the hypothesis that the magnitude and velocity of contraction depends on the type of Ca2+-release (non-propagating or propagating) and the "diffusional" size of the cell. We hypothesize that an increase in the cell circumference triggers a switch between non-propagating and propagating Ca2+-release, thereby providing a means for maintaining the speed and magnitude of contraction despite differences in cell size. Specifically, we test (1) that non-propagating Ca2+-release can elicit rapid and large contractions in atrial cells with small circumference. (2) Propagating Ca2+-waves are needed to cause rapid and large contractions in atrial cells with a large circumference. (3) The transverse axial tubular system (TATS), by reducing diffusional distances, allows non-propagating Ca2+-release to cause rapid and large contractions in large atrial cells. This proposal uniquely combines mathematical modeling, cellular electrophysiology and Ca2+ imaging and will provide a quantitative understanding of Ca2+ homeostasis in cardiac atrial cells.